The opioid receptors are important regulators of pain, reward, and addiction. Limited evidence suggests the mu and delta opioid receptors form a heterodimer (MDOR), which may act as a negative feedback brake on opioid-induced analgesia. However, evidence for the MDOR in vivo is indirect and limited, and there are few selective tools available. We recently published the first MDOR-selective antagonist, D24M, allowing us to test the role of the MDOR in mice. We thus cotreated CD-1 mice with D24M and opioids in tail flick, paw incision, and chemotherapy-induced peripheral neuropathy pain models. D24M treatment enhanced oxymorphone antinociception in all models by 54.7% to 628%. This enhancement could not be replicated with the mu and delta selective antagonists CTAP, naltrindole, and naloxonazine, and D24M had a mild transient effect in the rotarod test, suggesting this increase is selective to the MDOR. However, D24M had no effect on morphine or buprenorphine, suggesting that only specific opioids interact with the MDOR. To find a mechanism, we performed phosphoproteomic analysis on brainstems of mice. We found that the kinases Src and CaMKII were repressed by oxymorphone, which was restored by D24M. We were able to confirm the role of Src and CaMKII in D24M-enhanced antinociception using small molecule inhibitors (KN93 and Src-I1). Together, these results provide direct in vivo evidence that the MDOR acts as an opioid negative feedback brake, which occurs through the repression of Src and CaMKII signal transduction. These results further suggest that MDOR antagonism could be a means to improve clinical opioid therapy.
Opioid drugs like morphine are the gold standard for treating acute and chronic pain, but induce detrimental side effects such as tolerance and dependence. It has been suggested that the mu‐delta opioid receptor heterodimer (MDOR) transduces some of these side effects and that heterodimer targeted drugs could be a solution to weaken these side effects. We have thus created an MDOR selective antagonist called D24M. We evaluated D24M in vitro, and found a ~100 fold selectivity for the MDOR over the monomers. Similarly, we performed hot water tail‐flick experiments in mice in the presence of various doses of D24M against CYM51010 and Deltorphin‐2 (MDOR selective agonist), and DAMGO (MOR monomer selective agonist), and found that D24M potently (A50=2–7.8 nmol) blocked MDOR activity with no activity against the MOR monomer up to 10 nmol. To test the ability of D24M to lessen acute or chronic morphine‐induced dependence and withdrawal, we established acute (4 hr) and chronic (4 day) morphine dependence models, with 1 nmol D24M or vehicle injected 5 minutes prior to naloxone precipitation of withdrawal. We found that D24M strongly reduced jumping behavior in dependent mice in both the acutely and chronically models; further confirming that the MDOR promotes withdrawal behavior, and that D24M could possibly be a promising drug candidate for opioid dependence and withdrawal. These discoveries will further determine the role of the MDOR in vivo, and provide a novel tool that could greatly impact opioid heterodimer research.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
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